This proposal is designed to address the hypothesis that plasma fibronectin functioning in concert with phagocytic cells of the reticuloendothelial system (RES) acts as a significant antithrombotic mechanism. We hypothesize that this function is a determinant of a degree of deposition and embolization of material which results from activation of thrombotic mechanisms in association with vascular injury during systemic septicemia. We propose that plasma fibronectin acts as an antithrombotic agent by inhibiting certain interactions among fibrin, platelets and collagen which result in vascular deposition and aggregate formation. We further suggest that fibronectin augments RES phagocytosis of fibrin an platelets which results in their elimination from the vascular compartment. These activities are consistent with the finite number of demonstrated affinities for plasma fibronectin. These hypotheses will be studied by assessing the effect of fibronectin on the interaction of fibrin and platelets with collagen and vascular subendothelium and by assessing the effect of fibronectin on platelte aggregation as well a polymerization and solubility of fibrin. These studies will utilize in vivo and in vitro experimental models of sepsis, thrombosis and vascular injury. Further studies will assess the rate and capacity of the RES to clear fibrin and activated platelets from the circulation in normal, septic and experimental thrombotic states, as well as the relationship of plasma fibronectin to the rate and capacity of the RES to uptake fibrin and activated platelets from the circulation and in vitro. Further studies will assess the potential influence of degradation products of plasma fibronectin on the proposed opsonic and anti-thrombotic roles of plasma fibronectin. The proposed research may provide both basic information relative to the mechanisms by which fibronectin and the reticuloendothelial system may modulate thrombotic response and may additionally provide support for the concept that management of plasma fibronectin levels and reticuloendothelial function may be an important component of therapy for septic patients.